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J. Biol. Chem., Vol. 281, Issue 38, 28244-28253, September 22, 2006

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Biological Functions of Mammalian Nit1, the Counterpart of the Invertebrate NitFhit Rosetta Stone Protein, a Possible Tumor Suppressor^*

Shuho Semba, Shuang-Yin Han, Haiyan R. Qin, Kelly A. McCorkell^¶, Dimitrios Iliopoulos, Yuri Pekarsky, Teresa Druck, Francesco Trapasso^||, Carlo M. Croce, and Kay Huebner¹

From the Comprehensive Cancer Center and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, Stanford University Medical Center, Stanford, California 94305, ^¶Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ^||Department of Experimental and Clinical Medicine, Medical School of Catanzaro, "Magna Graecia" University of Catanzaro, 88100 Catanzaro, Italy

The "Rosetta Stone" hypothesis proposes that the existence of a fusion protein in some organisms predicts that the separate polypeptides function in the same biochemical pathway in other organisms and may physically interact. In Drosophila melanogaster and Caenorhabditis elegans, NitFhit protein is composed of two domains, a fragile histidine triad homolog and a bacterial and plant nitrilase homolog. We assessed the biological effects of mammalian Nit1 expression in comparison with Fhit and observed that: 1) Nit1 expression was observed in most normal tissues and overlapped partially with Fhit expression; 2) Nit1-deficient mouse kidney cells exhibited accelerated proliferation, resistance to DNA damage stress, and increased cyclin D1 expression; 3) cyclin D1 was up-regulated in Nit1 null mammary gland and skin; 4) Nit1 overexpression induced caspase-dependent apoptosis in vitro; and 5) Nit1 allele deficiency led to increased incidence of N-nitrosomethylbenzylamine-induced murine forestomach tumors. Thus, the biological effects of Nit1 expression are similar to Fhit effects. Adenoviruses carrying recombinant NIT1 and FHIT induced apoptosis in Fhit- and Nit1-deficient cells, respectively, suggesting that Nit1-Fhit interaction is not essential for function of either protein. The results suggest that Nit1 and Fhit share tumor suppressor signaling pathways, while localization of the NIT1 gene at a stable, rather than fragile, chromosome site explains the paucity of gene alterations and in frequent loss of expression of the NIT1 gene in human malignancies.

Received for publication, April 13, 2006 , and in revised form, July 21, 2006.

^* This work was supported by NCI, National Institutes of Health Grants P01 CA77738 (to K. H.) and P01 CA78890 (to C. M. C.), State of Pennsylvania Tobacco Settlement funds, by U.S. Department of Defense Breast Cancer Program Grant BC043090 (to D. I.), and by National Institutes of Health training grant T32-HLO7780 (to K. A. McC.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Table S1.

¹ To whom correspondence should be addressed: Comprehensive Cancer Center and Dept. of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, 455C Wiseman Hall, 410 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-4850; Fax: 614-292-3312; E-mail: kay.huebner{at}osumc.edu.

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